Asthma Flashcards
what is a drug history used as part of?
Used as part of medicines reconciliation
what are the 3 types of inhalers?
pMDI, dry powder and breath actuated
what group of patients is a pMDI useful for?
Good for majority of patients, but tricky for elderly and children
what group of patients is a dry powder inhaler useful for?
useful for patients over 5 years
What group of patients is a breath actuated inhaler useful for?
Better for older children and adults
describe the inhaler technique
First test inhaler by: removing cap; check dose counter, and point inhaler away from you and press canister once. To use:shake inhaler, make sure you are sat/standing upright with chin slightly tilted upwards, breath out gently away from the inhaler until lungs feel empty, then place mouthpiece between lips to form tight seal and start to breath in slowly and steadily. At the same time, press the canister once and continue to breath in until lungs feel full. Remove inhaler, and with lips closed, hold breath for up to 10 seconds then breath out. when finished, replace the cap.
why should you slightly tilt chin up when using an inhaler?
This helps the medicine reach the lungs better
explain the neural control of ventilation
Peripheral chemoreceptors detect changes in pH, pCO2 and pO2. Impulses are sent to respiratory centre via sensory nerves.
What is the normal heart rate range?
Between 60-100bpm
describe the regulation of ventilation
Respiratory centre consists of inspiratory and expiratory groups of neurons. These are regulated by the pneumotaxic centre.
describe what occurs during inhalation
The diaphragm contracts (moves down)
describe what occurs during exhalation
the diaphragm relaxes (moves up)
What is the importance of immunology?
many drugs use the immune system to treat diseases (autoimmune, cancer, allergic contact dermatitis)
Give examples of drugs used in immunology
monoclonal antibodies, anticytokine therapies
define immunology
the discipline of medicine concerned with: structure and function of immune system, innate and acquired immunity, and bodily distinction of self
what is key in immunology?
Communication
Give examples of physical and chemical barriers in immunology
skin, sebum, tears and sweat (lysozyme in tears), GI, respiratory and genito-urinary tracts are lined with mucous membranes which secrete mucous to trap microbes, ciliated epithelia in GIT to trap microbes, saliva and urine wash away microbes
What are the primary lymphoid tissues?
Bone marrow (B cells), thymus (t cells), lymphocyte development and haematopoiesis
What does the lymphatic system consist of?
primary lymphoid tissues, secondary lymphoid tissues, tertiary lymphoid tissues
What are secondary lymphoid tissues?
spleen, lymph nodes, gut associated lymphoid tissue and peyers patches, tonsils
What occurs in secondary lymphoid tissues?
Site where lymphocytes congregate and adaptive immune responses are initaited
what does the thymus consist of?
Cortex and medulla
Describe the structure of the cortex
packed with immature thymocytes from bone marrow
describe the structure of the medulla
cellular ‘mesh’ which makes up the thymus called stroma and comprises t-lymphocytes
what are the 2 major roles of the thymus?
- secretion of growth factors to mature thymocytes- maturation to t helper and t cytotoxic cells
- exposure of thymocytes to self epitopes on stroma- t cells recognising self die via apoptosis
Describe the structure of the spleen
Highly vascular and composed of red and white pulp (lymphoid tissue) and periarterial sheath (mostly t cells), has a marginal zone (many b cell follicles)
What are lymph nodes?
Immunological filter allowing contact between antigen and immune cells
what are lymph nodes composed of?
cortex, paracortex and medulla
what does the cortex consist of in lymph nodes?
dendritic cells presenting antigen and B cell follicles, where B cells proliferate
what does the paracortex in lymph nodes consist of?
many t cells
what occurs in the medulla of lymph nodes?
area of B cell antibody secretion
where are lymph nodes located?
adjacent to GI and respiratory tracts
what does malt stand for?
Mucosa associated lymphoid tissue
what are mucosa associated lymphoid tissue?
diffuse system of small concentrations of lymphoid tissue found in submucosal membrane sites
What do MALT consist largely of?
consists largely of groupings of lymphoid follicles
Give examples of MALT
Tonsils, appendix, peyers patches
what is essential for an effective immune system?
Communication between cells
what are the types of cells present in the immune system?
granulocytes, mononuclear cells, macrophages, dendritic cells, natural killer cells and NKT cells
Give examples of granulocytes
neutrophils, eosinophils, basophils and mast cells
give examples of mononuclear cells
lymphocytes, monocytes
what are the 2 types of immune response?
innate and adaptive immunity
what are the characteristics of innate immunity?
inborn and non specific
what does adaptive immunity consist of?
memory, specificity, and includes cell mediated and antibody mediated responses
Give examples of cells involved in innate immunity
dendritic cells, mast cells, macrophages, basophils
Give examples of cells involved in adaptive immunity
B cells, t cells, antibodies
Give examples of cells involved in both innate and adaptive immunity
T cells, Natural killer T cells
What are neutrophils and what is their role?
predominant granulocyte cell (consists of 60% circulating cells)
first cells to arrive at site of infection and engulf and destroy infectious agents
what are eosinophils and what is their role?
Contain cytoplasmic granules (eg. major basic protein) and eosinophil perioxidase
important for parasitic infections
What are basophils and what is their role?
minor cell population, role largely unknown but thought to play role in allergy through histamine release
what are mast cells and what is their role?
contain histamine and cytokines, and generate eicosanoids which are key to allergic reactions
What are B lymphocytes and what is their role?
Develop in bone marrow and mature in spleen
prior to antigen exposure, they are not yet producing antibody (naive)
after exposure, they proliferate and develop into plasma cells, producing increased levels of antibodies
where are T lymphocytes developed?
In the thymus
What are monocytes and what is their role?
precursors of tissue macrophages and dendritic cells
infiltrate tissue at site of infection and eliminate debris
What is the role of macrophages?
phagocytose unwanted material and then present the antigen to T cells
What are dendritic cells and what is their role?
have long dendrites that can interact with many cells
highly efficient antigen presenting cells, derived from myeloid or lymphoid
what are natural killer cells and what is their role?
large lymphocyte lineage cells which kill other cells on contact.
kills tumour cells and some virus infected cells and recognise targets by low/no MHC I expression.
react against microbial antigens
what is involved in immune cell signalling?
lipid mediators, polypeptide factors and cytokines
Give examples of lipid mediators?
eicosanoids, prostaglandins and thromboxanes
what side effects do platelet activating factors have?
muscle contraction, sleep disturbances
give examples of polypeptide factors
cytokines, complement and acute phase proteins
how do cytokines act?
act via autocrine, paracrine or signalling
define antigen
immunogen or a hapten foreign to body that evokes an immune response, either alone or after forming complex with larger molecule
what are antigens capable of?
capable of binding with product (as an antibody or t cell) of the immune response
‘the on/off switch of the immune system’
define epitopes
parts of the antigen recognised by the immune response
what is the goodness of fit of an antigen to antibody important for?
important in determining strength of binding
What could occur if an epitope is a low affinity binder to an antibody?
its possible that the antibody could bind to another similar epitope- cross reactivity
describe the factors contributing to immunogenicity of antigens
size (higher than 1kDA otherwise haptens), difference from self, dose and class (carbohydrate, lipid, nucleic acid and proteins)
what are antibodies?
soluble proteins that bind to antigens, can exist as membrane form and function as a B cell receptor
what are idiotypes?
antibodies which vary in the variable region
what does the variable region occupy?
occupies about 110 amino acids
what are the classes of antibody in humans?
IgM, IgD, IgG, IgE, IgA
What can produce the 5 classes of antibody?
B lymphocytes can produce all 5, but 1 at a time
what is IgG?
most abundant immunoglobulin in serum and consists of 4 subtypes (isotypes)
what are isotypes?
antibodies which vary in the constant region
What are the functions of IgG?
Transplacental transfer, agglutination, activation of complement, antibody dependant cytotoxicity, neutralisation and opsonisation
what is IgM and where does it exist?
Exists in 2 forms
- on surface of B lymphocytes as a single IgG like molecule
- in the circulating plasma as a pentameric (5 IgG like molecules) form
What are the functions of IgM?
very good agglutinator of antigens, foetal protection and activation of complement
What is IgA and how does it exist?
exists as a monomer or dimer with a J chain
What are the functions of IgA?
Protects mucosa- only antibody that can be secreted in any quantity across mucosa. to do so, it requires ‘secretory piece’ which acts as a suicidal transporter
neonatal protection from enteric pathogens
what is IgE and what are the functions?
similar to IgG but longer
Major role in asthma and allergy, and protection against parasitic infections
What is IgD and what are the functions?
produced along with IgG and serves as a B cell receptor and marker
Activates basophils to release antimicrobial factors
Describe the recognition of antigen by lymphocytes
Antigen binds to BCR or TCR to allow lymphocytes to proliferate and recognise the same antigen
what receptors regulate mucus secretion?
Muscarinic receptors
What are muscarinic receptors involved in?
muscarinic receptors are G protein coupled and are involved in: bronchoconstriction and increase mucus secretion at the neuroeffector junction
What are the main type of muscarinic receptors in the airways?
M3
does sympathetic innervation occur in the airways?
No sympathetic innervation although there are B2 adrenergic receptors that respond to adrenaline
what does the autonomic nervous system consist of?
Parasympathetic and Sympathetic nervous system
what are the functions of the lower respiratory tract?
distribution of air to alveoli, cleanse, warm and moisten air, and in mucus production
What surrounds bronchioles?
bronchioles have bands of smooth muscle surrounding airways
what does transmission at neuromuscular junction occur between?
occurs between a motor neuron and voluntary muscle
Forms part of the somatic nervous system
how does transmission at neuromuscular junction occur?
somatic motor neuron releases Ach at neuromuscular junction. Net entry of Na+ through Ach receptor channel initiates a muscle action potential
How does the regulation of intracellular Ca- occur?
Through negative feedback
what does curare cause?
causes muscle paralysis
what is tubocurarine used for?
a skeletal muscle relaxant to secure muscle relaxation in surgical procedures without deep anesthesia
give an example of a long acting non depolarizing muscle relaxant
Pancuronium
Give an example of an intermediate acting non depolarizing muscle relaxant
Atracurium, vecuronium, rocuronium
Give an example of a short acting non depolarising muscle relaxants
Mivacuronium
What is the mechanism of action of non depolarising muscle relaxants
bind nicotinic Ach receptors and competitively block acetylcholine, preventing muscle contraction
they are competitive antagonists
How can the block of acetylcholine be overridden in non depolarising muscle relaxants?
By the addition of cholinesterase inhibitors, which increases the concentration of Ach in synapse
What is the main use of non depolarising muscle relaxants?
Mainly used as an adjunct in anaesthesia
What are depolarising neuromuscular blockers?
Eg. Suxemethonium- not overcome by anti-cholinesterases
What are the 2 types of therapy used as a treatment for asthma?
controllers/preventers taken daily on long term basis to keep asthma under control, and relievers (rescue medication) used as needed to reverse bronchoconstriction
What are short acting beta 2 antagonists?
SABA, reliever- step 1
e.g salbutamol
What are long acting beta 2 antagonists?
LABA, preventers- step 3
e.g salmeterol and formoterol
define bronchodilate
relax airway smooth muscle and increase airflow to the lungs
What is the mechanism of action of beta 2 antagonists?
stimulate B2 adrenoreceptors and relax smooth muscle by raising cyclic AMP levels
What are the functions of beta 2 antagonists?
decrease production of inflammatory mediators from immune cells and increase mucocilliary clearance
What are inhaled corticosteroids classed as?
Preventers
When are inhaled corticosteroids used?
if a patient has experienced an exacerbation in the past 2 years; uses short acting beta 2 agonist 3< times per week; experiences asthma symptoms 3< times per week; wake up at least 1 night per week with symptoms
Give an example of an inhaled corticosteroid
Beclomethasone, fluticasone
What are oral corticosteroids classed as?
preventers
When would an oral corticosteroid be used?
High dose used in an acute attack, and lowest dose for adequate control of patients who suffer severe persistant/continuous symptoms
Give an example of an oral corticosteroid
prednisolone
What are the 2 actions of corticosteroids?
Anti inflammatory- stop release and formation of inflammatory substances (leukotrienes, prostaglandins)
immunosuppressive- stops proliferation and infiltration of white blood cells into inflamed areas
Name some side effects of oral corticosteroids?
hyperglycaemia, gastric ulcers, osteoporosis, cataracts, glaucoma, and brusing
Name some side effects of inhaled corticosteroids
Oral candidiasis, dysphonia and reflex cough
What are the main side effects of corticosteroids?
CORTICOSTEROIDS: Cushings syndrome osteoporosis retardation of growth thin skin and easily bruising infections and immunosuppression cataracts and glaucoma odema suppression of hypothalamic pituitary adrenal axis thinning and ulceration of gastric mucosa emotional disturbance rise in bp increase in hair growth others like fetal abnormalities and hypokalaemia diabetes mellitus precipitation stria
Describe step 3 of treatment of asthma
LABA used in combination with inhaled corticosteroid (never alone)
eg. Seretide: salmeterol and fluticasone; Symbicort SMART: budesonide and formoterol
what is step 4 of treatment of asthma?
Add on therapy
Give examples of add on therapy used in step 4
Methylxanthines, leukotriene antagonists, cromoglycates
What are oral/IV methylxanthines classed as?
Reliever and preventer, depending on formulation
Give an example of an oral/IV methylxanthine and when it would be used?
Theophylline (oral) used in step 5 and aminophylline (IV) used for acute exacerbations of asthma
Why is it important to use the same brand of theophylline in asthma treatment?
due to differences in bioavailability
What are the clinical effects of oral/IV methylxanthines?
- bronchodilation by: inhibiting breakdown of cAMP, and acting as an antagonist at adenosine receptors
- increased muco-ciliary clearance
- antiinflammatory effects- inhibits eosinophils
- reduces histamine and IL release from mast cells
Describe the theapeutic range of methylxanthines and what this may cause?
narrow therapeutic range- can cause seizures and arrhythmias
What are leukotriene receptor antagonists classed as?
preventer
Give examples of leukotriene receptor antagonists
Zafirlukast and montelukast
What are the functions of leukotriene receptor antagonists?
oral therapy taken at night. Relax airways and reduce mucus secretion, and inhibit exercise/aspirin induced asthma
What are lipoxygenase 5 antagonists used for?
prevent production of leukotrienes (eg zilutin)
little used due to liver side effects
What are cromoglycate and Nedocromil classed as?
preventers
How is cromoglycate administered?
given by aerosol inhalation, nebules and powder
how is nedocromil administered?
by aerosol inhalation, as it has no direct effect on smooth muscle given prophylactically
What are the roles of cromoglycate and nedocromil?
reduce bronchila hyper reactivity, and effective in antigen induced, exercise induced and irritant induced asthma
What must be noted before giving cromoglycate and nedocromil?
children more likely to respond than adults, and must be given before exposure to allergen
what is step 5 of asthma treatment?
daily oral corticosteroids at lowest dose possible for shortest amount of time
what is omalizumab classed as?
preventer
what is omalizumab and how is it administered?
monoclonal antibodies, brand name= xolair, given as injection every 4 weeks
what is omalizumab used for?
used to treat moderate/severe persistant asthma in those whose symptoms are not well controlled with inhaled corticosteroids
what is the mechanism of action of omalizumab?
binds free IgE in the serum, forming trimers and hexamers
drug binds to IgE at the same site that high affinity IgE receptor binds, so, IgE bound to drug cant bind its receptor on mast cells and basophils
what is the elimination half life of omalizumab?
7 days
where is omalizumab metabolised/eliminated?
by liver
describe the acquisition of antigen
foreign antigen enters body through skin, respiratory and GIT. Cells will pick up antigen and transport it to peripheral lymphoid tissues where adaptive immune responses are initiated
describe how adaptive repsonses occur?
antigen has to be presented to lymphocytes in organised lymphoid tissue by antigen presenting cells
what must immature dendritic cells do in adaptive responses?
immature Dendritic cells cant activate t cells, so must encounter antigen first, digest antigen into small peptide fragments
give examples of antigen presenting cells
macrophage, dendritic cells, langerhans cell
describe the process of dendritic cell maturation
immature dendritic cells become mature dendritic cells with increased MHC II and other receptors on its surface
what are dendritic cells responsive to?
cytokines and chemokines
what are the 4 main subfamilies that chemokines are grouped into?
CXC, CC, CX3C and XC
What is the role of chemokines?
these proteins exert biological effects by interacting with G protein coupled receptors, that are selectively found on the surface of target cells
what is the major histocompatibility complex MHC?
set of cell surface proteins essential for acquired immune system to recognise foreign molecules in vertebrates, which determines histocompatibility
what is the main role of MHC?
to bind to antigens derived from pathogens and display them on cell surface for recognition by appropriate t cells
also deterimines compatibility of donors for organ transplants and susceptibility ro an autoimmune disease
What are the 3 types of MHC?
MHCI, MHCII, MHCIII
What are the MHC class I genes?
HLA-A, HLA-B, HLA-C
what are the MHC class II genes in humans?
HLA-DP, HLA-DQ, HLA-DR
What are the MHC class III genes?
C2, C4 and factor b
encodes TNF and complement factors
how does the cleft size differ in MHC I and II?
type I= 8-10 amino acids long
type II= 12-18 amino acids long
Where is class I MHC found and what is its role?
found on all cells (except RBCs and neurons), known as transplantation Ag
presents endogenous Ag and interacts with CD8 on t cells
where is class II MHC found and what does it present?
found only on antigen presenting cells, presents exogenous Ag
interacts with CD4 on t cells
describe how MHC is involved in organ transplant process
determines whether an organ transplant is rejected or accepted
organ rejection is normal, as the immune response is directed towards non self MHC molecules
describe the role of MHC
t cell only recognises antigen when its presented by an antigen presenting cell that has a particular MHC molecule- MHC restriction
applies to CD8 t cells recognising MHCI and CD4 recognising MHCII
Where is CD4 found?
found on t helper cells
where is CD8 found?
found on t-cytotoxic cells
what does the relationship between MHC and CD4/8 define?
the type of immunological reaction
describe an endogenous antigen immune response
(intracellular-virus, parasite, cancer marker)- MHC class I presentation, CD8 and TCR recognition, activation T cytotoxic cells, killing of infected cells
describe what occurs in an exogenous antigen immune response?
(extracellular- bacterium, parasite, extracellular virus phase)- MHC class II presentation, CD4 and TCR recognition, activation of T helper cells, cytokines released to help B cells produce antibody
what are the 2 major pathways where antigens are processed and presented to t cells?
exogenous- taken up from outside the cell and presented to MHC II
endogenous- made up inside the cell and presented to MHC I
what are naive cells?
those which are meeting antigen for the 1st time
what are effector cells?
those which have gone through Ag stimulation and become activated, proliferate and ready to kill target cells
what other accessory molecules are involved in t cell activation?
LFA1-ICAM1 are adhesion molecules, CD28 is a critical receptor for B7-1 and B7-2 before stimulation
after stimulation, CD28 becomes CTLA-4 which inhibits further reactivity
What cells are involved in innate immunity?
polymorphonuclear leukocytes (PMNs, polymorphs, neutrophils), effector cells with cytotoxic granules (perforin/granzymes), M1 (pro inflammatory) and M2 (anti inflammatory), capture debris (APC)
describe the characteristics of polymorphonuclear leukocytes
very aggressive, short lived cells with characteristic multilobed nucleus
describe the characteristics of effector cells
rapid innate immunity
describe the role of M1 and M2 cells
promote angiogenesis and favour tumour progression
describe the role of capture debris
activates naive t cells
what is the role of epithelia?
impose physical barrier between body and external milieu
what do epithelial surfaces comprise of?
comprise of skin and linings of bodys tubular structures, GI, respiratory and urogenital Tract
describe the structure of the skin
outer layers of epidermis consists of the stratum corneum, which consists of dead corneocytes, full of keratin, seperated by lipid layers (landmann units).
this creates waterproof and impermeable layer
what occurs if keratinocytes are damaged?
produce TNF and IL-8 which leads to inflammation
what occurs on mucosal surfaces?
mechanical protection via a layer of mucus
what are mucosal surfaces used for in the airway?
the mucociliary escalator moves mucus and trapped particles to the throat to swallow
what is the role of the mucosal surfaces in the stomach?
the mucus protects gastric mucosa from stomach acid and enzymes
what is the role of the mucosal surfaces in the uterine cervix
protects uterus from bacterial invasion
breach by old style IUD threads could lead to pelvic inflammatory disease
what is the role of mucosal surfaces on the eyes?
on the eyes corneal surface, it protects the corneal epithelium
what occurs when a virus makes it into a cell?
antibodies cant bind to them anymore to prevent its entry, so something must be able to recognise virally infected cells and eliminate it
give examples of the types of T cells
T helper cells, cytotoxic lymphocytes and t regulatory cells
what is the difference between t cells and b cells?
t cells can also recognise antigens, but unlike b cells, these antigens can only be protein fragments
describe how t cells work
t cell receptor recognises and binds simultaneously to the foreign protein fragment and to the self protein (MHC) on the surface of affector protein cells
what are pattern recognition molecules and what are they used for?
IMS is armed with pattern recognition receptors that recognise pathogen associated molecular patterns (PAMPs) not found in host, then activates immune response
what are the 5 families that PRRs are classified into?
- toll like receptors (tLRs)
- nucleotide binding and oligomerisation domain (NOD) like receptors (NLRs)
- retinoic acid inducible gene 1 (RIG 1) like receptors (RLRs)
- C type lectins (CTLs)
- absent in melanoma (AIM) like receptors (ALRs)
where are TLRs and CTLs located?
in the plasma membrane
what are NLRs, RLRs and ALRs
intracellular PRRS
What are NLRs?
cytoplasmic receptors that play critical role in IMR by recognising PAMPs and damage associated molecular patterns (damps)
what 4 families does NLRs exist as?
NLRA, NLRB, NLRC, NLRP
what are the 4 functional categories that NOD-like molecules are divided as?
- inflammasome assembly
- signal transduction
- transcription activation
- autophagy
what are natural killer cells used for?
kill virally infected cells or tumours that have reduced MHC class I expression
what are the chemokines responsible for as inflammatory mediators?
group of peptides responsible for control of migration of leukocytes (noming) in the respective anatomical locations in inflammatory and homeostatic processes
how are chemokines up regulated?
by number of cytokines involved in infection and inflammation
- y interferon and TNF-a
what are the 4 types of chemokines?
CC type, CXC type, CX3C type and C type
what are the 4 types of chemokines produced by and what do they affect?
produced by number of cell types and affect mostly leukocytes (especially lymphocytes) via chemokine receptors
what are the 5 chemokine functions?
- monocytes/macrophages (eg CCL chemokines CCL2)
- t cells (CCL2, CCL1, CCL22, CCL17)
- mast cells- express several receptors for chemokines (CCR1, CCR2, CCR3, CCR4, CCR5, CXCR2, CXCR4)
- eosinophils- migration of eosinophils into tissues involves CCL11, CCL24, CCL26, CCL5, CCL7, CCL13 and CCL3)
- neutrophils- regulated mostly by CXC chemokines
what occurs following t cell activation in regards to chemokines?
CXCR3 expression is induced
activated t cells are attracted to sites of inflammation, where the inducible chemokines CXCL9, CXCL10 and CXCL11 are secreted
why are ligands of receptors CCL2 and CCL5 important?
play important role in mast cell recruitment and activation in lung
how do CCL11 and CCL5 act?
through CCR3 on surface of eosinophils
why is eotaxin (CCL11) important?
plays role in initial recruitment of eosinophils into the lesion
what is the role of CXCL8?
a chemoattractant for neutrophils and also activating their degranulation
what is the complement system?
part of immune system that enhances ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promoting inflammation and attacks membrane
what is the complement system a part of and what is it made up of?
part of IMS
made up of number of small proteins (consists of 30 soluble proteins) found in blood, synthesised by liver and normally circulating as inactive precursors (pro-proteins)
what happens when complement system is stimulated?
proteases in system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages
what is the complement system designed to do?
an effector mechanism designed to kill target cells and regulates inflammatory responses by enhancing phagocytosis and WBC recruitment
what are many components of the complement system secreted as?
many components secreted as zymogens and are activated by proteolysis
what are the 3 pathways complement activation occurs?
- classical pathway- activated by antibody attached to antigen
- alternative- activated by cell surfaces unable to inhibit complement
- lectin- activated by mannose binding lectin
what was complement discovered as?
discovered as a heat labile component of plasma which augment the opsonisation and killing of bacteria by antibodies
define opsonisation
coating of pathogen by antibodies or complement proteins, so its readily destroyed by phagocytic cells
What does complement also influence?
influences AIS (t and B cells)
what does complement system recognise?
recognises features of microbes and marks them for destruction by phagocytes by C3b
What does the classical pathway of complement activation require?
requires presence of antibodies (IgM or IgG)
when is the lectin pathway initiated in complement activation?
initiated during inflammatory responses upon contact with bacterial surfaces
what are the 2 types of pulmonary drug delivery?
local and systemic
what are the characteristics of local delivery
rapid onset of action, small doses
give examples of systemic delivery
inhaled anaesthetics, insulin
give examples of local delivery
B2 agonists, corticosteroids, anticholinergics
what can be used to help drugs get into the lungs?
inhalers, nebulisers
name the different types of inhalers
pMDI, DPI, and soft mist inhalers (respimat)
define aerosol
a 2 phase system of solid particles or liquid droplets dispersed in air or other gaseous phases
what does airway deposition depend on?
- physicochemical properties of drug- particle size, shape and density
- formulation- pMDI, dry powder
- delivery/liberating device- aerosol velocity
- patient- breathing patterns, clinical status
define aerodynamic
the dynamics of bodies moving relative to gases, especially the interaction of moving objects with the atmosphere
define aerodynamic diameter
the physical diameter of a spherical particle with unit density (1g cm-3) that has the same inertial properties (terminal settling velocity) in the gas as the particle of interest
equation to calculate aerodynamic diameter
Da= dp(P/Po)^1/2 dp= physical diameter Po= unit density p= particle density
what are therapuetic aerosols classed as
heterodisperse
what is the distribution of sizes represented by in mass median aerodynamic diameter?
represented by geometric standard deviation, when size is log-normally distributed
when dp is mass median diameter, what is Da?
da= Mass median aerodynamic diameter
what does particle deposition depend on?
aerodynamic diameter
what are the mechanisms of particle deposition?
inertial impaction, sedimentation, brownian diffusion, interception
what is the probability of deposition via impaction dependent on?
dependent on momentum of particle and also proportionate to angle: VtVsino/Gr Vt= terminal settling velocity o= change in airway direction V= air stream velocity r= airway radius
equation for momentum of particle
momentum= mass x velocity
what is sedimentation
setlling under gravity, airflow is low
where does impaction take place?
upper tracheobronchial region
what is stokes law
Vt= pgd^2/18n Vt= terminal settling velocity p= particle density g= gravitational constant d= particle diameter n= air viscosity
where does sedimentation occur in the lungs?
small airways and alveoli
what is sedimentation dependant on?
dependent on particle size and density and residency time in the lung
where does diffusion take place in the lung?
in the alveoli
describe the particle density of large porous particles
physical diameter-20um and density- 0.4gcm-3
efficient deposition in the lungs
what do breathing patterns depend on?
inhaled volume, flow rate of inhalation, breath holding and airway disease
Describe what was found in lung deposition studies
assesed regional distribution of inhaled compound
quantify patients influence on deposition
use technetium labelled drug and use gamma scintigraphy
provide a picture of deposition
what are the different methods of aerosol size analysis?
- gamma scintigraphy- in vivo direct measurement
- microscopy- in vitro, labour intensive, not moving air stream
- laser diffraction- in vitro, volume median diameter
- cascade impaction- in vitro, aerodynamic particle diameter
describe what an anderson cascade impactor involves
known flow rate, 90 degree bend and generally has 8 stages. involves metal collection plates and terminal filter
what are the disadvantages of anderson cascade impactors
- high flow rates- rapid solvent evaporation, particles bounce off collection surfaces
- constant air flow rate- not representative of in vivo
- time consuming
what are the 3 main types of aerosol generating devices?
- pressurised metered dose inhalers
- dry powder inhalers
- nebulisers
- technique depends on the device being used
describe the material containers of pMDIs
must be chemically inert
tin plated steel, plastic coated glass, uncoated AL, Al with internal coating of epoxy resin or PTFE
extruded al to avoid seams
can withstand internal pressure of >400kPa
capacity= 10-30ml
describe what a pMDI propellant is and how they work
Liquified gases (CFCs replaced by HFAs), work though a constant pressure system and producing a consistant spray
what is the evaporation of a liquid?
saturated vapour pressure
how are formulations generally made up?
generally made up of blends of the propellants together to give an intermediate vapour pressure of 450kPa
what does the blending of propellants include?
include a surfactant (eg sorbitan trioleate, oleic acid) which acts as a suspending agent for the drug and lubricates the valve
describe the solubility of surfactants in the blending of propellants
poorly soluble in HFAs
give examples of hydroflourocarbons
HFA134a (triflouromonoflouroethane), HFA227 (heptaflouropropane)
describe the characteristics of hydroflourocarbons
non ozone depleting, non flammable, density similar to CFC12 and CFC114, but poor solvents for surfactants commonly used in MDI formulations
describe how ethanol may be used with HFAs
ethanol is approved for use in formulations containing HFAa tp allow dissolution of surfactants, but has low volatility and may increase droplet size of emitted aerosol
what effect does a smaller particle size have?
smaller particle size can change pulmonary distribution and bioavailability
what is Rauoults law and ideal mix of liquids?
the partial vapour pressure of a component in a mixture is equal to the vapour pressure of the pure component at that temperature multiplied by its mole fraction in the mixture
equation for Raoults law
p= pA + pB
p= total vapour pressure of system
pA and pB= partial vapour pressure of components A and B in the mixture
equation for partial vapour pressure
PA= XA x P^oA Xa= mole fraction P^oA= partial vapour pressures of A and B as if they were on their own
what is the vapour pressure of a mixed system equal to?
equal to the sum of mole fraction of each component multiplied by its vapour pressure
describe what a pMDI metering valve is and how it is used
reproducible delivery of small volumes (25-100ul)
used inverted and needs to be primed
affects shape and speed of aerosol plume
what are the formulations of pMDIs?
solutions or suspensions of drug in liquefied propellant
describe the properties of pMDIs formulated as solutions
2 phase systems- propellants are poor solvents, cosolvent (eg ethanol) have low volatility
describe the properties of pMDIs formulated as suspensions
3 phase systems- caking, agglomeration and particle growth
particle size, valve clogging, moisture content, relative density of drug and propellant
what are the 3 ways of filling pMDI canisters?
cold filling, pressure filling and leak testing
describe the process of cold filling pMDI canisters
drug excipients and propellants chilled to -60C, and canister then sealed with valve
describe the process of pressure filing pMDI canisters
concentrated solution or suspension of drug in propellant, under pressure filled into canisters via the valve
describe the process of leak testing to fill pMDI canisters
water bath at 50-60C, weighing after storage prior to insertion into actuators and spray testing
what are the advantages of pMDIs
portable, many doses, reproducible dose delivery, low cost, disposable, inert conditions
what are the disadvantages of pMDIs?
inefficient drug delivery, incorrectly used, and small doses
describe why pMDIs may present inefficient drug delivery
upon actuation: high velocity- drug lost due to impaction, mean emitted droplet size >40um, and propellant evaporation slow (5 seconds to achieve desired particle size)
describe some areas where patients may incorrectly use a pMDI
failure to remove cap, used upside down, failure to shake canister, failure to inhale slowly and deeply, inadequate breath holding, poor inhalation/actuation synchronisation
how much of the drug is emitted in pMDI if correct technique used?
only 10-20% of emitted dose is delivered to site of action
what are spacers useful for?
reduce droplet velocity, permit efficient propellant evaporation, and remove the need for actuation/inhalation coordination
how are breath actuated pMDIs activated?
actuation triggered during inhalation
describe the process of adjusting surface roughness of carrier particles
- microionised drug trapped- low inhaled dose
- microionised drug readily released- may release during filling of device
- microionised carrier particles to fill rough voids-drug readily released
what are the advantages of DPIs
propellant free, only 1 excipient (lactose), breath actuated (avoids problems coordinating inhalation with actuation of pMDI), can deliver larger doses than pMDIs, which are limited by size of metering valve
what are the disadvantages of DPIs?
delivery dependent on patients ability to inhale, turbulence can increase inertial impaction in upper airways, formulation less stable than pMDIs, less efficient than pMDIs
name the different DPI devices
- unit dose devices with drug in hard gelatin capsule- spinhaler, cyclohaler
- multidose devices with drug in foil blisters- diskhaler (GSK)
- multidose devices with drug preloaded in inhaler- accuhaler, clickhaler
when are nebulisers used and how do they work?
deliver relatively large volumes and inhaled during normal tidal breathing.
alternative to pMDI and DPI if: drug cant be formulated, or dose is too large
what are the 3 main types of nebulisers?
jet nebulisers, ultrasonic nebulisers, vibrating mesh nebulisers
describe the formulation of nebuliser fluid
in water: cosolvents, surfactants (suspensions), stabilizers (antioxidants, preservatives)
iso-osmotic, pH= 3-10
usually sterile isotonic unit doses
what are the types of data
categorical- (lived/died, underweight/normal/obese)
numerical (age/height/number of medications)
why is the use of data important?
describes sample and makes an inference about the population
what is numerical data?
- discrete data that can be counted
2. continuous data that can be measured
how would you summarise data
categorical data= %
numerical data= mean- measure of the average
- also want a measure of variability
how could you compare 2 means?
null hypothesis- mean 1=mean 2
experimental hypothesis- mean 1< mean 2 and vise versa
what are inferential statistics?
go beyond describing the sample and is a decision tool for rejecting null hypothesis
what are the test hypotheses in inferential statistics?
statement about the predicted outcome of study and states the independent and dependant variable
what does inferential statistics tell us about probability?
will tell you the probability that the effect observed is due to random factor (p value)
what does a p value of 1 mean?
100% probable that the effect wouldve occured under the null
what does a p value of 0.5 mean?
50% probable that the effect wouldve occured under the null
what does a p value of 0.05 mean?
5% probable that the effect wouldve occured under null
equation for paired t test
t= d/Sd(root of n)
what is an independent t test used for?
2 seperate groups
what types of groups could you use an independent t test for?
experimental groups- drugs vs placebo, hot conditions vs cold
naturally occuring groupings (quasi experimental)- young vs old, males vs females
when would data violate a parametric assumption?
not normally distributed, unequal variance, ordinal data
what would be used instead if data violates a parametric assumption?
use Mann whitney test instead
what are t tests used for
to compare the difference between 2 mean scores
what is the adaptive immune system and what is it used for?
the 2nd level of protection that is activated to enhance the innate system
what does the adaptive immune system mainly consist of?
mainly consists of lymphocytes
what are lymphocytes and what is their role?
white blood cells that have the ability to recognise a unique part of a microorganism, memorise it and produce specific pathogen neutralising compounds known as immunoglobulins
so when the body encounters this particular antigen again, it can prodyce more of the immunoglobulins it knows can kill it
what is a naive CD4 + t cell called?
THO cell
what does exposure to antigen cause for a THO cell?
exposure to antigen causes differentiation of a THO cell to form t helper subset: Th1, th2, th17, Tregs and Tfh
what is the main factor in determining which subset will be produced in the differentiation of THO cells
cytokines- these subsets are characterised by cytokines they produce and promote different kinds of immune responses
what is the function of TH1?
Key for cell mediated immune responses and important against intracellular bacterial infections and viruses
what is the function of TH2 cells?
key for production of antibodies and control of extracellular bacteria and parasitic worms
what is the function of th17?
key for cell mediated defense against extracellular bacterial infections via neutrophils
what is the function of Treg cells?
key for suppressing immune responses and maintenence of tolerance
what are the functions of Tfh cells?
acquire expression of CXCR5 and important in antibody production
what will CD4+ cells differentiate into?
will differentiate into short lived effector cells or long lived memory cells
what do effector cells provide?
provide immediate defense against antigen
what do memory cells provide?
confer protection after re-exposure to antigen
how do effector and memory cells differ?
differ by surface marker expression
eg. effector cells express CD69, memory cells express CD45RA
how does a t cell receptor recognise antigen?
recognises antigen only if it is presented by an MHC molecule on he surface of an antigen presenting cell
what group of immune receptors is TCR similar to?
immunoglobulin superfamily
what are B lymphocytes responsible for?
dont kill anything directly, make antibodies
what is the role of antibodies secreted by b lymphocytes?
antibodies bind to foreign molecules which neutralise their effects. also bind to bacteria which signals other host immune proteins and cells to kill
antibodies secreted by b cells also have a membrane bound form of the antibody on their surface- this antibody acts as a receptor which recognises antigen and through signal transduction process, helps activate B cell
what can mature B cells do?
can make lots of antibodies quickly, as they have seen antigen before
where does B and T cell interaction occur
occurs in paracortex of lymph nodes
describe the process of B and T cell interaction
b cell internalises antigen on b cell receptor and presents fragments of the antigen on MHC II molecules to t cell
what does b and t cell interaction require?
needs 2 signals binding of TCR to MHC through CD40 and antigen binding to b cell receptor
what are the 2 types of b cell response to Ag?
- thymus dependent response- requires t cell help to deliver antigen to b cell follicles
- thymus independent response- doesnt need t cell help
eg. TLR ligands and microbial polysaccharides that cross link b cell receptors
what is class switch recombination?
high affinity b cells can interact with antigen specific t cells and under the influence of t cell derived cytokines, undergo isotype switching
what is the isotope produced in class switch recombination highly dependent on?
highly dependent on cytokine made by t cell
describe the generation of CD8+ responses
CD8+ cytotoxic t lymphocyte responses (similar to CD4 response)
APCs acquire antigen process and present on MHC class I molecules
antigen MHC I and signal 2 via CD28 which to B7 on APC
what is required for CD8+ responses
requites 2 signals for activation
what is proliferation dependent on in CD8+ responses
dependent on IL-2
what are effector t cytotoxic cells responsible for?
can kill any cell expressing the antigen concerned in association with MHC I
what do granules consist of in CD8+ cell killing?
perforins and granzymes
what is the role of perforins?
secreted next to target cell and assemble to form pores in cell membrane, allowing the granzymes to enter target cell
what is the role of granzymes?
interact with target cells to initiate apoptosis
when does primary immune response occur and what happens after elimination of antigen?
maximal within 10 days of antigen exposure
after elimination of antigen, 90% of cells die, 10% from memory b and t cells
what do memory cells ensure?
that the immune response acts more robustly upon re-exposure to antigen
when do secondary immune responses occur?
maximal within 4 days of re-exposure to antigen hallmark of adaptive immunity
describe adherence to inahlers
low rates of adherence to controller inhaler associated with hospitalisations and mortality
estimated 50% adherence overall chronic conditions
30-70% adherence to asthma medications
children <50%
what are the reasons for non adherence
intentional, motivation, non drug reasons, non intentional, ability, drug reasons
difficulty with inhaler devices, side effects
describe the needs vs concerns evidence
there is evidence that patients make decisions about medicines based on their understanding of their condition and the possible treatments, their view of their own need for the medicine and their concerns about the medicine
what strategies can be used for improving adherence?
involve patients in decision making (concordance), provide a rationale for regular use, elicit and address concerns, address the practical barriers in a consultation
what is the new medicines service and what is it for
advanced service that is recently extended. it is a pharmacist led consultation that aims at: providing support for people with long term conditions newly prescribed a medicine to help improve medicines adherence, and to increase patient understanding
what does treatment of asthma require?
requires combination of pharmacology and psychology
why are pharmacist led reviews important
offer place for pharmacists to target non adherence
define tolerance
immunological non reactivity to an antigen, due to lack of response of lymphocytes when exposed to specific antigens
what could tolerance result from?
- deletion- after antigen exposure, lymphocytes may recieve signal to die
- antigen exposure may render lymphocytes non responsive
- immunological ignorance- antigen may not be immunogenic
what is central tolerance
process where B and T cells rendered non responsive to self antigens during development in bone marrow and thymus
expression of the Aire gene in thymic medullary epithelial cells is critical for t cell tolerance
major mechanism where autoreactive lymphocytes are removed/silenced so they cant attack self tissues
can lymphocytes escape tolerance?
some lymphocytes escape tolerance and must be tolerated in the periphery
where can b and t cells both be tolerated?
both can be tolerated in the periphery
what could failure to delete autoreactive CD4 result in
may result in cell mediated and antibody mediated autoimmunity
how can peripheral tolerance occur
may occur as a result of:
- deletion- t cells commit suicide (apoptosis), usually as a result of repeated antigen stimulation
- anergy (inability to respond)- usually due to lack of co-stimulatory molecules during antigen presentation (stops presentation of antigens by ‘resting’ antigen presenting cells)
- suppression- eg Tregs
what is the mechanism of deletion?
best characterised in the phenomenon of activation induced death by repeated Ag stimulation- occurs when recently activated t cells are repeatedly reactivated
in such situation, t cells express Fas and Fas ligand which binds to each other and induce apoptosis
what type of mechanism is deletion?
probably a regulation mechanism, but some pathogens shed large amounts of free Ag to stimulate this mechanism
describe the mechanism of action of anergy
mechanism to prevent response to resting APCs. APCs up regulate co stimulatory molecules when actively phagocytosing pathogens and presenting Ag
- the most important is B7 but rather than expressing CD28, some t cells will express CTLA-4
what happens when t cells express CTLA-4 in the mechanism of tolerance of anergy?
CTLA-4 when binding to B7 induces anergy. once induced, this type of anergy will persist, even if offered an MHC restricted Ag with B7 co stimulation (normal presentation)
describe the mechanism of tolerance of immune ignorance
not all self antigens expressed in thymus or bone marrow- some will be in immunologically previledged sites
these will not normally be seen by immune system during life, so no reactivity
eg. lens protein in eye, some heart muscle epitopes
what problems can immune ignorance cause?
can perhaps cause a problem in trauma to that organ, releasing Ag into circulation
when do autoimmune diseases occur?
breakdown of tolerance is a pre requisite for development of autoimmune diseases.
autoimmune diseases occur when adaptive immune responses to self antigens contribute to tissue damage
what 2 classes are autoimmune diseases divided into?
- systemic- eg. scleroderma, systemic lupus erythematosus
2. organ specific- eg. graves disease, myasthenia gravis, ms
how does graves disease occur?
autoantibodies produced against TSH receptors on surface on thyroid cells.
antibody acts as an agonist and stimulates production of thyroid hormones, leading to overactivity of thyroid glands
what is hypersensitivity?
an immune response that occurs in an exaggerated form causing damage to host tissues
what are the 4 types of hypersensitivity responses?
- type 1- (allergy) immediate involving IgE
- type II- (cytotoxic hypersensitivity) antibody initiated
- type III (immune complexes)- between antibody and antigen
- type IV (delayed type)- mediated by t cells and macrophages
describe type 1 hypersensitivity
recognised as allergy and people with a genetic predisposition to allergy (atopic)
allergy may be local (reaction to cosmetic) or systemic (reaction to distributed drug)
Known that upon first meeting allergen, no reaction occurs (priming dose) but subsequent encounters cause the reaction (shocking dose)
what is the key immunological reaction in type 1 hypersensitivity?
involvement of mast cells and IgE isotope of antibody
how does damage occur in type 1 hypersensitivity?
damage is via inflammatory like reactions
what is the difference between type 1 hypersensitivity local and systemic reactions?
local reactions are uncomfortable, but systemic can be life threatening, with reaction usually in a matter of minutes from meeting inducing factor (allergen)
- suggests pre formed elements are involved
what are the symptoms of allergy
nose: sneezing, itching, runny
eyes: redness, itching
lungs: coughing, wheezing, shortness of breath
skin: eczema, hives
GIT: pain, vomiting, diarrhoea, bloating
what is anaphylaxis and when does it occur?
dramatic allergic reaction with onset rapid symptoms within 15-30 mins
death may occur within a further 15 mins, and persons advised to carry epinephrine pen- raises bp and reduces swelling of airways
how can allergies be diagnosed
- skin prick test- diluted potential antigen given under skin, wheal and flare reaction within 15-30 mins
- blood test- Elisa to detect IgE levels
what is a distinguishing feature of type II hypersensitivity?
distinguishing feature is an antibody (IgM or IgG) response to cell surface bound antigens
- these may be pathological, or may be normal but unwanted, as in blood group transfusion reactions
give an example of type II hypersensitivity
usually quoted as haemolytic disease of the newborn
how does damage occur in type II hypersensitivity
damage is usually via complement activation and cell lysis
what is the difference between type II and type I hypersensitivity
can appear as drug induced type 1 but is much slower, and due to drug binding to cell surface proteins to form a neoantigen
what is the distinguishing feature of type III hypersensitivity?
involvement of immune complexes, so always involves a soluble antigen
can be autoimmune or non self antigen
how does damage occur in type III hypersensitivity
damage usually via complement activation and inflammatory response
how long does a type III hypersensitivity reaction take to develop
as with type 2, reaction takes days to develop
how long does type IV hypersensitivity reactions take to develop?
slowest of all 4 types, takes 1-2 days to develop
what is the distinguishing feature of type IV hypersensitivity?
only type caused by the cell mediated response with involvement of Th1, macrophages and Tcyt cells, but not antibody
may be autoimmune or caused by non self antigen
how does damage occur in type IV hypersensitivity
damage is via CD8 cell and macrophage activity
give an example of type IV hypersensitivity and what what it can cause?
nickel allergy
can cause chronic disease, but type example is the tuberculin reaction
what does chronic inflammation cause?
causes an associated increase in airway hyper responsiveness and leads to recurrent episodes of wheezing, breathlessness, chest tightness and coughing
what is chronic inflammation and what does it lead to
a chronic inflammatory disorder of the airways, leading to reversible airway obstruction
symptoms occur early morning or at night
what is IgE and what is it used for?
immunoglobulin E is a class of antibody
plays an essential role in type 1 hypersensitivity, which presents during various allergic diseases
also plays a role in allergic conditions, such as anaphylactic reactions to certain drugs/bee stings
present in minute amounts in body, but capable of triggering most powerful inflammatiion reactions
what is the role of IgE in asthma?
binds to allergens and triggers release of substances from mast cells that can cause inflammation
what is allergen exposure
repeated exposure to particular allergen can be 1st step in developing a reaction to it
what is t cell action
allergens induce t cells to activate b cells which develops into plasma cells that produce and release more antibodies
name the classifications of asthma
- extrinsic (atopic/allergic)
- intrinsic (non atopic)
- based on phenotypes
- eosinophilic/non eosinophilic
what is the extrinsic classification of asthma?
an external trigger that can be identified, childhood asthma, IgE mediated against common environmental antigens (dust, pollen)
acute symptoms
hereditary in 40-60% of cases
what is the intrinsic classification of asthma?
no obvious causative agent, tends to occur after childhood
more chronic symptoms
describe the classification of asthma based on phenotypes
eg. allergic (IgE) such as dust mites
non allergic such as pollution, aspirin sensitive, occupational asthma and exercise induced asthma
describe the eosinophilic/non eosinophilic classification of asthma
type of white blood cell whose natural role is to defend body against parasites
also accumulate wherever allergic reactions take place
where do eosinophils gather and what are they responsible for
gather wherever there is a parasitic infection/allergic reaction and then release chemicals
the chemicals are very efficient at fighting parasites, but they can also harm the body if released in the wrong place
- the lining of lungs becomes damaged in asthma
what are the 2 categories of precipitating factors
IgE related- specific precipitating factors, and non IgE related- non specific precipitating factors
give examples of IgE related precipitating factors
animal allergens- labs/farms, flour/grains- farms/bakers, enzymes- washing powders
give examples of non IgE related precipitating factors
isocyanides- spray painting, cold air and exercise, airborne irritants (cigarette smoke, fumes, pollution), irritant dust, vapours and fumes, drugs- NSAIDs, beta blockers, infections of the respiratory tract, emotional factors such as stress or laughter
what are bronchial provocation tests?
increased responsiveness of airways, as measured by a lower FEV/PEFR to stimuli such as inhaled histamine and methacholine
what is FEV1?
forced expiratory volume- volume of air that can forcibly be blown out in 1 second after full inspiration
what is PEF
peak expiratory flow- maximal flow achieved during the maximally forced expiration initiated at full inspiration, in L/min or L/sec
what does exposure to allergen lead to in pathogenesis
- a single exposure to allergen causes a dual asthmatic response
- repeated exposure to allergens leads to chronic inflammation and bronchoconstriction
what are the 2 phases of an asthma attack?
acute/early phase response (acute bronchospasm)
late phase response (inflammation)
what is the acute/early phase response in an asthma attack?
exposure to allergen results in bronchospasm and wheezing within minutes
maximal effect reached within 15-20 minutes and effect subsides after 1-3 hours
may then progress to late phase
describe the late phase response in an asthma attack
develops about 4 hours after initial acute phase and may last for further 6-8 hours
characterised by eosinophilia in the mucus membrane, mucosal oedema and increases smooth muscle excitability (hyper responsiveness)
airways obstruction with cough and sputum production
what changes occurs during a reactive airway disease episode?
- increased mucus- airways become irritated and inflamed, causing cells in airways to produce mucus (thick mucus produced can clog airways of lung, making it difficult to breath)
- inflammation and swelling- airways of lungs swell and become inflamed
- muscle tightening- smooth muscles in airways of lungs tighten and airways become smaller, making it more difficult to breathe
what is histamine and how does it work?
organic nitrogenous compound involved in inflammatory response
increases permeability of capillaries to white blood cells and some proteins, to allow them to engage pathogens in infected tissues
exerts its effects by binding to G protein coupled histamine receptors, designated H1 through H4
What are the functions of histamine
elicits vasodilation, smooth muscle contraction, mucus hypersecretion and oedema, as part of immediate phase allergic reaction
also has significant immune/proinflammatory properties that are mediated by several cell types (macrophage, t lymphocytes, epithelial and endothelial cells)
what does chronic inflammation cause
causes airway hyper responsiveness
what does chronic inflammation involve
involves a host of white blood cells: mast cells, eosinophils, lymphocytes and macrophages
what occurs upon mast cell degranulation
arachidonic acid metabolites (leukotriene, prostaglandins and cytokines) release occurs
what are cytokines and why are they important
proteins that are produced by cells
critical elements of immune response and acts as a signal between cells
interact with cells of immune system in order to regulate bodys response to disease and infection
describe the roles of cytokines in asthma
tumour necrosis factor and interleukin 4, IL5, IL6, IL1B, IL13 profound effects on vascular endothelium (eg. alteration of vascular permeability and adhesiveness) allowing circulating inflammtory cells to adhere to the endothelium and to migrate into surrounding tissue IL4, 5 and 6 stimulate the proliferation and differentiation of activated b cells and induces class switch IL5 is also important in stimulating growth and differentiation of eosinophils
describe the process of cell adherence
- mast cell progenitors must migrate from the blood into tissue sites- crucial step is adherence of cells to endothelium
- mediated by adhesion molecules and receptors on surface of mast cells that can mediate binding to other cells and to extracellular matrix
- TNF-a and IL4 can modulate adhesion molecules on endothelial cells
- activated endothelial cells express the intracellular adhesion molecule, endothelial leukocyte adhesion molecule 1, and vascular cell adhesion molecule on their cell surface
- human mast cells express integrins as receptors for these molecules
give examples of neutral proteases that mast cells produce and the role of other mast cell mediators
eg. tryptase and chymase that damage and activate the bronchial epithelium, contributing to airway wall remodelling
key in host defense, with role in immune surveillance, phagocytosis and immune activation
what is a characteristic feature of asthma
tissue remodelling
how do mast cells affect airway remodelling
mast cells may have affect on tissue remodelling on smooth muscle hypertrophy and on mucus hyper secretion, by releasing proteases (tryptase) and growth factors
these cells can also affect epithelial damage, and on basement membrane thickening in patients with allergic asthma
how is ongoing mast cell activation detected in asthma
detected by elevated levels of tryptase and PGD2 in bronchoalveolar lavage (BAL)
describe the clinical characteristics of mast cell degranulation
higher spontaneous release of histamine by mast cells obtained from the BAL of asthmatics is observed than those obtained from non asthmatics
ultrastructural analysis of mast cells in lung tissue also shows that asthmatics have more degranulation than atopic non asthmatics
what are autocoids? what are they released by?
substances produced within the body to help in the remedy of local injuries- locally acting biological factors which are hormone like
released by various stimuli to induce physiological changes such as reddening of the skin, pain, itching, bronchospasm
-these effects can sometimes be undesirable and cause cell death
usually have very brief lifetime and act near site of action
what are the functions of autocoids?
- inflammation
- allergic reactions, anaphylactic reactions
- neurotransmission
- gastric acid secretion
- neuroendocrine regulation
- have CNS properties, they are responsible for bp control
what signs of inflammation can autocoids cause?
rubor (redness), tumor (swelling), calor (heat) and dolor (pain)
what are the 4 types of inflammation
- type 1- anaphylaxis or allergy
- type 2- antibody dependent cytotoxicty
- type 3- complex mediated hypersensitivity
- type 4- cell mediated hypersensitivity
what are the classifications of autocoids?
- endogenous amines- histamine, seratonin
- polypeptides- angiotensin, kinins
- lipid derived autocoids- prostaglandins, leukotrienes, thromboxane
what is histamine synthesised from and what is it released by
synthesised from histidine, stored in granules in mast cell or basophils and released by allergens
what does the activation of mast cells release
release granules of histamine and heparin
how can histamine release occur
allergenvia IgE, trauma, side effects of drugs (morphine)
what are kinins and how are they synthesised
peptide mediators (eg bradykinin), synthesised from kininogen and metabolised by kinases
what are the actions of kinins
pain, swelling and redness
- vasodilation and smooth muscle constrictor
- via a bradykinin receptor (releases eicosanoids- prostaglandins)
what are eicosanoids made of and what are their roles
signalling molecules made by oxidation of 20 carbon fatty acids
complex control over inflammation or immunity and as messengers in CNS
- platelet activating factpr
- prostaglandins, leukotrines
what do mast cells release
histamine, leukotrienes, prostaglandin D2, PAF, TNFa, kallikrein
what do antihistamines do and give examples of antihistamines
block H1 receptor a 7TMG protein coupled receptor
- eg. chlorphenamine, hydroxyzine and promethazine (drowsy)
- cetirizine, loratidine and fexofenadine (non drowsy)
describe the properties of the platelet activating factor
1st phospholipid known to have messenger functions
derived from membrane bound lipids in basophils, monocytes, neutrophils and platelets
continuously produced but in low amounts and production is controlled by activity of PAF acetylhydrolases
produced in larger quantities by inflammatory cells
what are the functions of PAF
- activates platelets
- bronchospasm
- chemotactic for white blood cells
- hyperalgesia (dolor)
- odema (tumor)
what are prostaglandins and what do they consist of
group of hormone like lipid compounds that are derived enzymatically from fatty acids
contains 20C atoms, including a 5 carbon ring
what is the role of prostaglandins
mediators of many physiological effects such as regulating the contraction and relaxation of smooth muscle tissues
act in an autocrine or paracrine manner
hyperalgesia- sensitise nerve endings to painful stimuli
inflammation: dilate arterioles, constrict venules, increase capillary permeability and leakiness
what is the role of prostaglandins in the stomach
decrease acid secretion and increase mucous secretion (gastroprotective)
what is the role of prostaglandings in kidneys
increase blood flow and increase Na+ and H2O excretion (diuretic)
what are the vascular effects of prostaglandins
vasodilation and inhibit platelet aggregation
what are the therapeutic uses of prostaglandins
obstetrics, gastric ulcers, glaucoma
what are non steroidal anti inflammatory drugs
anti inflammatory, analgesics and antipyretics
types: ibuprofen, naproxen, diclofenac, aspirin
what are the side effects of NSAIDs
- peptic ulcers- inhibit gastric protection by prostaglandins
- renal damage (papillary necrosis)- decreases renal blood flow, causing salt and water retention
- hypertension
- headaches
- allergic reactions
what is cyclooxygenase and what are their roles?
enzymes that produce prostaglandins
2 types of COX enzymes
COX 1 and 2 produce prostaglandins that promote inflammation, pain and fever
what is a feature of only COX 1 enzymes
only COX 1 produces prostaglandins that activate platelets and protect the stomach and intestinal lining
describe the effect that NSAIDs have on COX enzymes
NSAIDs block the cox enzymes and lower the production of prostaglandins
how are inflammation, pain and fever decreased
lowered by all cox inhibitors
what do older NSAIDs block? what do newer NSAIDs block?
both COX 1 and 2
newer cox 2 inhibitors only block cox 2 enzyme
what is a benefit of using newer cox 2 inhibitors
since cox 2 inhibitors dont block cox 1, they dont cause ulcers or increase risk of bleeding as much as older NSAIDs
cox 2 inhibitors are as effective as older NSAIDs for treating inflammation, pain and fever
how are leukotrienes produced and what do they trigger?
by the oxidation of arachadonic acid and the essential fatty acid, EPA, by the enzyme lipooxygenase
triggers contractions in smooth muscles lining the bronchioles
what is the overproduction of leukotrienes a cause of?
major cause of inflammation in asthma and allergic rhinitis
what do leukotrienes use to communicate with cells
use lipid signalling to communicate to the cell producing them (autocrine) or neighbouring cells (paracrine) to regulate immune responses
what are leukotriene antagonists
used to treat asthma by inhibiting the production or activity of leukotrienes
eg. montelukast, zafirlukast
what is the most important glucocorticosteroid
cortisol- binds to the GR and activates gene transcription
also non genomic effect
eg. src kinase binds to inactive GR, released via cortisol binding and phosphorylates proteins, resulting in decreased creatin of AA
What do corticosteroids do
lower inflammation in airways that carry air to lungs and lower the mucus made by bronchial tubes, making it easier to breath
regulates/supports variety of cardiovascular, immunological, metabolic and homeostatic functions
various synthetic glucocorticosteroids are available and used as either replacement therapy in glucocorticosteroid deficiency or to suppress immune system
what are the anti inflammatory effects of glucocorticosteroids?
- increase lipocortin- inhibits phospholipase A2
- decreases cox2 expression
decreases cytokine production
decreases IgG production
inhibits macrophages and neutrophils
lowers t helper cell activity
describe the aetiology of COPD
- Genetic factors- a1 antitrypsin deficiency
- age
- occupation
- air pollution
- socioeconomic status
- biggest risk factor= smoking
what is meant by one pack year
smoking 20 cigarettes per day for one year
number of pack years= (number smoked per day x number of years smoked/20)
what are the characteristics of pink puffer type A
- increased alveolar ventilation
- PaO2
- lowers PaCO2
- breathless
describe the properties of blue bloater type B
- decreases alveolar ventilation
- lowers PaO2
- Lowers Paco2
- not breathless
- rely on hypotoxic drive to maintain respiration as their respiratory centres are desensitised to increased PaCO2
what are the clinical symptoms of cOPD
Cough, sputum and dyspnoea
what are the signs of COPD
tachypnoea, hyperinflation, wheeze, cyanosis, cor pulmonale
what are the complications of COPD
acute exacerbations +/- infection, polycythaemia, cor pulmonale, respiratory failure
how is COPD assessed
- spirometry
- bronchodilator response
- trial of oral steroids
- CXR
describe the non pharmalogical treatment of COPD
- stop smoking
- exercise
- influenza and pneumococcal vaccine
describe the pharmacological treatment of COPD
- mild COPD- antimuscarinics (eg. ipatropium inhaled prn)
- moderate- regular antimuscarinics or long lasting B2 agonist
- inhaled steroid if FEV1<50%> 2 exacerbations per year - severe- combined therapy, regular short acting b2 agonist with ipatropium
- consider steroid trial
- assess for home nebuliser
what treatment options would be suggested for more advanced COPD
- pulmonary rehab (multidisciplinary team)
- theophylline (monitor levels)
- consider LTOT if PaO2 <7.3 kpa
- check home support
- treat depression
describe the management of acute exacerbations of COPD
- controlled o2 therapy start at 24-28% monitor ABG
- nebulised bronchodilators salbutamol and ipatropium
- steroids IV hydrocortisone and oral prednisolone
antibiotics for infection - physiotherapy to aid sputum expectroration
- if no response, repeat nebulisers, IV aminophylline
what is involved in the diagnosis of asthma
- clinical assessment involving history of recurrent episodes
- symptoms of wheeze, cough and breathlessness
- personal and family history
- no symptoms/signs to suggest alternate diagnosis
what are the signs and symptoms of asthma
wheezing, cough, shortness of breath, tightness in chest and night time awakenings
name the lung function tests
FEV1, FVC (forced vital capacity), PEF
Bronchodilator administered and would expect to see increase in FEV1
name the treatments used for asthma
SABA: salbutamol used as reliever of symptoms
ICS: beclomethasone used as preventor of symptoms
LABA: salmeterol used as additive treatment
LTRA: montelukast used as additive treatment
what determines whether asthma is controlled vs uncontrolled
based on symptoms and frequency of symptoms
less symptoms= more controlled
what is the step down guidance
adults stable on high dose ICS should reduce dose by 25-50% every 3 months
- regular reviews to ensure overtreatment doesnt occur
points to consider: severity, benefits seen from treatment, length of treatment and patients preference
